3-Pyridineacetic acid → Risedronate

HRID 1823657Notes

Reaction equation

HRID 1823657 reaction equation
Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:3]=1.[P:12]([OH:15])([OH:14])[OH:13].N1C=CC=C(CC(O)=O)C=1.[OH:26][PH:27]([OH:29])=[O:28].P(Cl)(Cl)(Cl)=O>O.C1(C)C=CC=CC=1>[CH:6]1[CH:7]=[N:2][CH:3]=[C:4]([CH2:8][C:9]([P:27]([OH:29])([OH:28])=[O:26])([P:12]([OH:15])([OH:14])=[O:13])[OH:11])[CH:5]=1

Participants

8

Reactant 5

HCID 1083-Pyridineacetic acidHCID 407Phosphonic acidHCID 24813Phosphorus oxychlorideHCID 107909Phosphorous acidHCID 27237243-Pyridineacetic acid, hydrochloride (1:1)

Product 1

HCID 5245RisedronateYield 71%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 1140TolueneSolvent

Conditions

Temperature
90 °C

Procedure

A 2L cylindrical reactor equipped with a mechanical stirrer, a thermometer, a reflux condenser and a dropping funnel, was charged with 3-pyridine acetic acid hydrochloride (27.7 g, 0.16 mole), phosphorous acid (39.4 g, 0.48 mole) and toluene (200 ml). The suspension was heated to 90° C. Hyfllo Super-Cel diatomaceous silica (70 g, 50% w/w of all the reagents) was added in portions after the mixture of 3-pyridyl acetic acid and H3PO3 was melted, to obtain an heterogeneous suspension. Phosphorous oxychloride (44.8 ml, 0.48 mole) was then added dropwise during 12 minutes. The reaction mixture was then heated to 95° C. for 3 hours. Water (300 ml) was added after cooling the reaction mixture to 65° C. The mixture was stirred vigorously for 30 minutes and then the Hyfllo was removed by filtration. The toluene and the aqueous phases were separated and the aqueous phase was heated at 95° C. for 16 hours. The aqueous phase was cooled to 25° C. and absolute ethanol (300 ml) was added to precipitate the final product. The suspension was cooled to 5° C. for 1 hour. The white product was filtered, washed with absolute ethanol (2×80 ml) and dried in a vacuum oven at 50° C. for 24 hours to obtain 31.7 g (71%) of risedronic acid monohytdrate.

Workup

  1. additionHyfllo Super-Cel diatomaceous silica (70 g, 50% w/w of all the reagents) was added in portions
  2. customto obtain an heterogeneous suspension
  3. temperatureThe reaction mixture was then heated to 95° C. for 3 hours
  4. temperatureafter cooling the reaction mixture to 65° C
  5. customthe Hyfllo was removed by filtration
  6. customThe toluene and the aqueous phases were separated
  7. temperaturethe aqueous phase was heated at 95° C. for 16 hours
  8. temperatureThe aqueous phase was cooled to 25° C.
  9. additionabsolute ethanol (300 ml) was added
  10. customto precipitate the final product
  11. temperatureThe suspension was cooled to 5° C. for 1 hour
  12. filtrationThe white product was filtered
  13. washwashed with absolute ethanol (2×80 ml)
  14. customdried in a vacuum oven at 50° C. for 24 hours

Sources & evidence

ORD record
ord-e3ae148a513245edb486b130c7e0d4a8
Source dataset
uspto-grants-2006_05
Patent number
US07038083B2

Reaction notes

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